: Liver transplantation is curative in patients with unresectable hepatocellular carcinoma (HCC). However, the clinical need for organs greatly exceeds their availability. In addition, few patients diagnosed with HCC are candidates for primary surgical resection, due to an insufficient future liver remnant (FLR) in the presence of underlying liver disease. Portal vein embolization (PVE), a technique known to induce FLR hypertrophy by redirecting portal flow, is relatively contraindicated in cirrhosis due to concerns to induce liver failure and worsen pre-existent portal hypertension following the procedure. We have recently demonstrated the potential efficacy of a new paradigm to achieve locoregional HCC control while inducing FLR hypertrophy with lobar infusion of 90Y impregnated glass beads (90Y radiation lobectomy [90Y-RL]). Although preliminary data demonstrates the utility of this approach, the optimal dose strategy to induce FLR hypertrophy while minimizing the risk of worsening liver function and portal hypertension is unknown. Our proposed study investigates the underlying mechanisms of embolized liver atrophy and FLR hypertrophy following 90Y-RL through improved dosimetry and advanced quantitative MR imaging. Patients with unresectable HCC will be recruited at the time of referral for 90Y-RL following review in our multidisciplinary HCC treatment conference. In Aim #1 we will investigate the influence of proscribed radiation dose and glass bead embolic load on FLR hypertrophy calculating actual parenchymal doses with the use of non-FDG PET/CT to visualize glass bead distribution following 90Y-RL. The optimal dose/embolic load paradigm will be applied in a prospective study of 64 subjects with unresectable HCC referred for 90Y-RL in Aim #2. These subjects will undergo quantitative MR imaging, assessing changes in liver stiffness with MR elastography, liver hemodynamics with non-contrast 4D flow MRI, and parenchymal perfusion with accelerated time-resolved MR angiography before and at 1- and 3-months after 90Y-RL. Quantitative MRI derived biomarkers will be correlated with FLR hypertrophy and trophic factors to delineate changes predictive of adequate FLR following 90Y-RL. Finally, we will assess differences in recurrence-free survival 90Y-RL patients who underwent surgical resection and those whose FLR deemed them candidates for surgical resection at presentation. This project will deepen our understanding of the mechanisms leading to the liver atrophy- hypertrophy complex following 90Y-RL endeavoring to make the procedure safer and more effective. The results of this study will support a multicenter clinical trial evaluating the survival of patients with unresectable HCC treated with 90Y-RL.